Brain insulin receptors link stress and metabolism.

Abstract

In this issue of Molecular Metabolism, Chong et al. [1] observed altered functioning of the hypothalamic–pituitary–adrenal (HPA) axis in mice lacking insulin receptors (IR) in selected regions of the brain. The rationale was to push beyond the original report of altered HPA activity in mice lacking IR in all brain neurons (NIRKO mice) [2] by assessing animals lacking IR in more targeted neuronal types. Specifically, male mice lacking IR broadly in forebrain areas, including most of the hypothalamus (IRNkx2.1 KO mice), had enhanced anxiety-like behavior on several tasks as well as elevated basal plasma arginine vasopressin (AVP) and increased secretion of corticosterone (CORT) in response to physical restraint. To determine the impact of IR knockout in specific populations of hypothalamic neurons, HPA axis function was also assessed in IRSim1 KO and IRAgrp KO male mice. In IRSim1 KO, the IR should be absent in the paraventricular and supraoptic nuclei (as well as a few extrahypothalamic areas) [3]. These mice manifested no changes of HPA activity or related behavior, implying that neurons located within the PVN (and/or SON) that express IR are unlikely to be the source of the stress phenotypes observed in IRNkx2.1 KO mice. There was a phenotype involving the HPA axis in male IRAgrp KO mice that appeared superficially to be somewhat opposite to that observed in IRNkx2.1 KO mice, including reduced basal AVP and reduced CORT in response to restraint. From these data, Chong et al. concluded that signaling through IR on AgRP-expressing neurons increases responsivity of the HPA and AVP systems.